Doxorubicin, a cytotoxic drug used as an anticancer drug, and the like targets the cell cycle, so that the toxicity is dependent on the degree of cancer cell proliferation. Also, it is generally used near the maximum allowable dose to obtain its clinical treatment effect. However, these anticancer drugs kill rapidly proliferating cells, but fail to differentiate normal cells from cancer cells or cancerous tissues, and kill other cells other than cancer cells and cause side effects such as vomiting when they are used at high concentrations. In addition, the long-term treatment can cause tolerance to an anticancer drug, and thus, it is urgently required for improved therapies in which a cytotoxic drug targets and only kills cancer cells.
Meanwhile, many attempts have been made to improve the efficacy of cytotoxic drugs by increasing the local concentration of the drug by conjugating an antibody to a tumor-associated antigen with a cytotoxic agent and delivering it to a specific tumor. Many of these methods have achieved limited success and problems to address these failures have been discussed in literature. For example, for chemotherapeutic anticancer agents such as doxorubicin or methotrexate, relatively high intracellular concentrations are required to exert the expected cytotoxicity. These concentrations are believed to be difficult to achieve using many antibody-drug conjugates due to (a) inadequate efficacy of many common anticancer agents, (b) low antigenic target concentrations on the cell surface, (c) ineffective internalization of antigen-antibody complexes into target cells, and (d) the inefficient release of drugs liberated from the conjugate within the target cells.
Therefore, there is an increasing need for target-oriented drug delivery immunoconjugates capable of delivering drugs at relatively high drug concentrations in target cells, by specifically delivering cytotoxic drugs to target cells and alleviating drug side effects to normal cells.